Prostaglandin derivatives and process for the preparation thereof

ABSTRACT

Prostaglandin derivative having the formula   WHEREIN R represents a straight or branched alkyl group having from one to eight carbon atoms, R1 represents hydrogen atom or 2tetrahydropyranyl group, R2 represents hydroxy group, A represents a straight or branched alkylene group having from one to eight carbon atoms, X represents trans-CH CH- and Y represents cis-CH CH- and the pharmaceutically acceptable salts thereof. The protaglandin derivatives are useful as uterine contracting agents and may be prepared by reacting a compound having the formula   WHEREIN R, R1, R2 and X are the same as above with an alkali metal salt of a phosphorane compound having the formula

United States Patent 1 Sakai et al,

[111 ,Tnly 6,11975 22 Filed: Dec. 4, 11973 21 Appl. No: 421mm Related U.S. Application Data [63] Continuation-in-part of Ser. No. 292,513, Sept 27,

1972, abandoned.

[30] Foreign Application Priority Data July 5, 1972 Japan 47-67342 [52] U.S. Cl 260/240 R; 260/343.5; 260/468 D;

260/468 .l; 260/514 1; 424/283; 424/317 [51] hit. Cl. C07c 611/32 [58] Field of Search 260/240 R, 514 D [56] References (Iited UNITED STATES PATENTS 7/1972 lFinch 260/514 D 8/1973 Caton et al. 260/514 D Primary ExaminerArthur P. Demers Attorney, Agent, or Firm-Flynn & lFrishauf [57] ABSTRACT lProstaglandin derivative having the formula wherein R represents a straight or branched alkyl group having from one to eight carbon atoms, R represents hydrogen atom or Z-tetrahydropyranyl group, R represents hydroxy group, A represents a straight or branched allcylene group having from one to eight carbon atoms, X represents trans-CH=Cl-l and Y represents cis-CH=Clll and the pharmaceutically acceptable salts thereof. The protaglandin derivatives are useful as uterine contracting agents and may be prepared by reacting a compound having the formula wherein R, R, R and X are the same as above with an alkali metal salt of a phosphorane compound having the formula 6 (R PCl-lACOOl-l wherein A is the same as above and R represents a hydrocarbon group and, if desired, hydrolyzing the reaction product.

4 Claims, No Drawings PRUSTAGLANDTN DERIVATIVES ANT) PRIOCESS FUR THE PREPARATTQN THEREOF RELATED APPLICATION This application is a continuation-in-part of application Ser. No. 292,513, filed Sept. 27, 1972, now abandoned.

This invention relates to novel prostaglandin deriva tives which are useful as uterine contracting agents and to a process for the preparation thereof.

More particularly, it relates to prostaglandin derivatives having the formula i ca wherein R and R are the same as above.

The dotted line attachment shown in the above and below formulae indicates that the substituent is in the oz-configuration, i.e., is below the plane of the cyclopentane nucleus and the solid line attachment indicates that the substituent is in the ,B-configuration, i.e., is above the plane of the cyclopentane nucleus. The wavy line attachment indicates that the substituent is in the 01- or ,8- configuration.

The pharmaceutically acceptable salts of the compounds of this invention include salts of alkali or alkaline earth metals such as sodium, potassium, magnesium and calcium, quaternary ammonium salts such as ammonium salt, tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, phenyltriethylammonium salt; salts of aliphatic, alicyclic or aromatic amines such as methylamine, ethylam ine, dimethylamine, diethylamine, trimethylamine, triethylamine, N-methylhexylamine, cyclopentylamine,

dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine and ethylenediamine; salts of heterocyclic amines or lower alkyl derivatives thereof such as piperidine, morpholine, pyrrolidine, piperazine, pyridine, l-methylpiperazine and 4-ethylmorpholine; salts of amines being water soluble or containing a hydrophilic group such as monoethanolamine, ethyldiethanolamine and Z-amino-l-butanol. These salts may be prepared by conventional procedures described in the chemical literature.

As a result of earnest investigations for prostaglandin derivatives, we have unexpectedly found that the com pounds having the formula (l) exhibit uterine contraction activity. For example, l5-hydroXypr0sta-5(cis), l3(trans)-dienoic acid (Example 2) exhibits in final concentrations of 37 ug an equivalent contraction activity of smooth muscle to that of prostaglandin E in final concentrations of 0.1 ug [tested by Magnus method using rat uterine smooth muscle]. And pregnant rat uterus at term is contracted for 15 minutes by intravenous injection of 0.1 mg./kg. of lS-hydroxyprosta-S (cis), l3(trans)-dienoic acid (Example 2) or 200 ug/kg. of 11a, IS-dihydroxyprosta-S (cis), l3 (trans)- dienoic acid (Example 3) respectively.

The present compounds (I) may be administered, for example as a sodium salt, by continuous intravenous injection dissolved in isotonic sodium chloride solution. The dosage is different depending upon the body weight and ages of a patient, but generally the total daily dosage for pregnant women at term is of about 10 mg 400 mg.

According to the process of the present invention, the compound having the formula (I) can be prepared by reacting a compound having the formula GHQ wherein R, R, R and X are the same as above with an alkali metal salt of a phosphorane compound having the formula (R 3 TEE-"#0003 (III) wherein A is the same as above and R represents a hydrocarbon group and, if desired, hydrolyzing the reaction product.

The process of the present invention may be preferably carried out by contacting the compound (Tl) with the phosphorane compound (H1) in a molar ratio of 1: about llO in the presence of an inert organic solvent. It is preferable to use an excess amount of an alkali metal salt of the phosphorane compound. The phosphorane compound (Ill) is often referred to as Wittig reagent and the group R in the formula (III) is preferably an aryl group, e.g., phenyl or an alkyl group having l6 carbon atoms, e.g., methyl, ethyl and n-butyl. The phosphorane compounds (lllli) can be prepared by known process in the art and obtained as salts of alkali metal such as sodium and potassium. Therefore, the alkali metal salts of the phosphorane compound (Ill) are usually employed in the present process. As a solvent, there may be employed any inert organic solvent without limitation that would be usually employed in a Witethanol, ethers, e.g., tetrahydrofuran arid dioxane and mixture of water and said organic solvent.

The reaction temperature is not critical and the reaction is usually carried out within a range of from room tig reaction. Examples of suchasolvent include etherS, 5 temperature to reflux temperature of a solvent eme.g., diethyl ether, tetrahydrofuran and dioxane; hydroployed, preferably at room temperature. carbons, e.g., benzene, toluene and hexane; dialkyl sul- The reaction period is varied mainly depending upon foxide, e.g., dimethyl sulfoxide; and halogenohydrocarthe reaction temperature and a kind of the reactant. bons, e.g., dichloromethane and chloroform. .When the reaction is carried out at room temperature, The reaction temperature is not critical and the reacthe reaction period is from about within one hour to ten tion is usually carried out at from 0C to a reflux temhours. After completion of the reaction, the reaction perature of the solvent employed, preferably at room product is separated from the reaction mixture by a temperature. The reaction period is varied mainly deconventional means. For instance,-the desired product pending upon the reaction temperature and a kind of is separated by distilating off the solvent from the reacthe reactant. When the reaction is carried out at room [5 ti i t Th product is, if necessary, further puritemperature, the reaction period is from about 30 minfired by a conventional means, for example, column utes to 40 hours. After completion of the reaction, the chromatography and thin layer chromatography. When reaction product is separated from the reaction mixture the elimination step is carried out in a strong acidic by a conventional means. For instance, the reaction condition, a dehydration reaction occurs as well as the mixture is poured into ice water and the mixture is elimination reaction. made acidic by addition of an acid such as acetic acid In the process of this invention, the compounds (I) and oxalic acid. The mixture is extracted with asuitable can be obtained as a mixture of four optical isomers solvent such as ether and ethyl acetate and the solvent caused by the configurations of the side chains atis distilled off to give the desired product. The product tached to the cyclopentane nucleus and the configurathus obtained is, if necessary, further purified by a contions of the hydroxy group attached to the side chain. ventional means, for example, column chromatography These racemic mixtures can be resolved at appropriate and thin layer chromatography. stages by method well known in the art, whereupon w the group in the f l (I) is tetrahydro subsequent products may be obtained as the correpyranyl group, the group may be, if desired, eliminated Spondmg p y P d lastereo'lsomer s- In the forum" by treating the compound (I) with a weakly acidic solulac (1)) and both dlastefeolsomenf forms as tion as the racemic forms are depicted by a single represen- AS the aeidie Solution, there may be employed an tation. However, it should not be considered to limit ganic acid solution such as formic acid-, acetic acid-, the Scope of the dlsclosure propionic acid-, butyric acid-, oxalic acid-, and malonic The compounds p yF as a Stamng Platenal acid solution and a dilute inorganic acid solution such a novel and Prepared accordmg to the followmg reacas a dilute hydrochloric acidand a dilute sulfuric acid ,tlon Sequence; solution. As the solvent, there may be employed an 1- P a O 0 the compound in which R2 is inert solvent such as water, alcohols; e. g., methanol and hy r g n atom O Q/jr -01 ,515 coon O with KOH Angenandte Ghemie estarification oocu oxidation with with CH N on chronic acid-pyridine compie coocir inversion wlth coocn basic alumina CH0 liit'big reaction 00005 reduction with (1142 11 P ca-g-R 1:32:1

R-CH-X reduction with l O THP (iso C I-I AIH OIH Ho (XI) X R II o THP Weakly CHO acidic solution x CH R In the above formulae, R and X are the same as above, 20 Th c mp und (XI) d (1]) may b prepared b R represents an alkyl group and THP represents 2- tetrahydropyranyl group.

The compound (V) may be prepared by subjecting the compound (IV) to catalytic reduction with palladium on charcoal. The reduction is preferably carried out in an inert solvent, e.g., water, methanol, ethanol and ether at room temperature.

The compound (VI) may be prepared by contacting the compound (V) with boron halide, e.g., boron trichloride and boron tribromide. The reaction is preferably carried out in an inert organic solvent, e.g., dichloromethane and chloroform at a temperature ranging from 50C. to room temperature, usually at C.

The compound (VII) may be prepared by oxidizing the compound (VI) with chromic acid-pyridine complex. The reaction is preferably carried out in an inert organic solvent, e.g., acetic acid, dichloromethane and chloroform at a temperature ranging from 0C. to room temperature.

The compound (VIII) may be prepared by reacting the compound (VII) with a Wittig reagent having the formula At least one mole of the Wittig reagent is used per mole of the compound (VII) and preferably from 2 to moles of the Wittig reagent is used. The reaction is generally carried out in an inert organic solvent, e.g., ether, benzene and chloroform at a temperature ranging from 0C. to a reflux temperature of the reaction.

The compound (IX) may be prepared by reducing the compound (VIII) with sodium boron hydride. The reduction is preferably carried out in an inert organic solvent, e.g., methanol, tetrahydrofuran and ether at a temperature ranging from l0C. to room temperature.

The compound (X) may be prepared by contacting the compound (IX) with dihydropyran in the presence of p-toluenesulfonic acid. The reaction is preferably carried out in an inert organic solvent, e.g., chloroform, acetonitrile and benzene at a temperature ranging from 0C. to room temperature.

ducing the compound (X) with diisobutylaluminum hydride. The reduction is preferably carried out in an inert organic solvent, e.g., methanol, ethanol, tetrahydrofuran and benzene at a temperature ranging from C. to room temperature.

The compound (II) may be prepared by treating the compound (XII) and/or (II) with weakly acidic solution such as a dilute solution of acetic acid, hydrochloric acid or sulfuric acid.

The product obtained in each step of the above process may be recovered from the reaction mixture in a conventional manner, for example, by evaporating the solvent from the reaction mixture or by adding water to the reaction mixture and extracting with a waterimmiscible solvent. The crude product can be purified by conventional means such as recrystallization or chromatography.

The following preparations, examples and referential examples are given for the purpose of illustration of the present invention.

Preparation of 2- I 2B-[ 3-( Z-tetrahydropyranyl )oxy-trans- 1 -octenyl 3a-hydroxycyclopent-la-yl ethanol (II) and 2- 2B-( 3-hydroxyl -trans-octenyl )-3 a-hydroxycyclopent-la-yl] ethanol (II) 1. l-hydroxy-2-methoxymethyl-3-acetic acid cyclopentane-l ,3(8)-lactone (V).

In 19 ml. of ethanol is dissolved 5 g. of l-hydroxy- 2-methoxymethyl-3-acetic acid cyclopent-4-enel,3(6)-lactone (IV) and to the solution is added dropwise 3 g. of 5% palladium on charcoal in 108 ml. of ethanol. The mixture is subjected to catalytic reduction in a hydrogen atmosphere.

After completion of the absorption of hydrogen gas, the catalyst is filtered off from the reaction mixture and the solvent is distilled off from the filtrate under reduced pressure to give 4.75 g. of oily residues. The residues are subjected to column chromatography using 50 g. of silica gel and eluted with some amount of benzene and next successively with l 15 percent solution of ether in benzene. The eluations from the latter solvent are collected and the solvent is distilled off to give 4.2 g. of the desired product as oil.

dihydropyran p -tdoluensulfonic X-CH-R ,E

reduction with oxidation with acidic solution Preparation at.v the comp enund (I i) n wh h R jish hydroxf grou p v.

izocl-l v RocH catalytic reduction- -with palladium on charcoal "axid'a'ti'on with I p HocH c i I boron trihalogen i'de chromic acidpyridine complex 0 W ittig' reaction: v

dihydrapyran -O THP p-tolu'enlesulfonicx acid redaction 9 6.64 (3H, singlet, OC

5.2 (1H, broad, [93

2. 1-hydroxy-2-hydroxymethyl-3-acetic acid cyclopentanel ,3()-lactone (Vll).

A solution of 4.9 g. of l-hydroxy-2-methoxymethy1- 3-acetic acid cyclopentane-l,3(5)-lactone (V) in 50 m1. of dichloromethane is cooled to a temperature ranging from -45C. to C. and to the solution is added dropwise a solution of 35.8 g. of boron tribromide in 30 ml. of dichloromethane. After completion of the addition, the temperature of the reaction mixture is slowly elevated to 0C. and the mixture is stirred for 2 hours at 0C. After completion of the reaction, aqueous sodium bicarbonate is added to the reaction mixture to precipitate white oils. To the reaction mixture is added Rochelle salt and the mixture is extracted with chloroform. The solvent is distilled ofi to give 3.9 g. of the desired product as oil.

LR. (liquid film) v -cm 3470, 1725 NNLR. (@100 'r: ppm

6.56 (2H, doublet, -CH OH) 5.2 (1H, multiplet,

Mass spectrum M 156 (Cd-11 0 0.9 in, -c

4. 1-hydroxy-2-(3-oxo-trans-1octenyl)-3-acetic acid cyclopentane-1,3(5)-lactone (V111).

To a solution of 0.69 g. of l-hydroxy-2-formyl-3- acetic acid cyclopentane-1,3(5)-lactone (VII) in 10 ml. of ether is added 1.8 g. of 2-oxoheptylidene-tri-nbutylphosphorane and the solution is stirred at room temperature for 5 hours. After completion of the reaction, the solvent is distilled off to give 2.6 g. of oily residues.

The residues are subjected to column chromatography using 26 g. of silica gel and eluted with some amount of hexane 40% solution of benzene in hexane and next successively with 5070% solution of benzene in hexane. The eluates with the latter solvent are collected and the solvent is distilled off to give 2.2 g. of oily residues.

The residues are further subjected to column chromatography using 20 g. of silica gel and eluted with some amount of hexane 40% solution of benzene in hexane and next successively with 50-70% solution of benzene in hexane. The eluates with the latter solvent are collected and the solvent is distilled off to give 1.2 g. of the desired product as oil.

LR. (liquid film) v cm' z 1745, 1675 NJVJLR. (CDCI T' ppm 5.25 (1H, multiplet 0 O Si 3.75 (1H doublet, J 16 cps. CO-C'aZ=CBI-) 3.40 (1H, double doublet, J 16 cps...

.co ?=ci H .2 Mass spectrum M63: 250 c n o 5. 1-hydroxy-2-( 3-hydroxy-trans- 1 -octenyl )-3-acetic acid cyclopentane-l ,3(5)-lactone (1X).

To a solution of 0.83 g. of 1-hydroxy-2-(3-hydroxytrans-1-octenyl)-3-acetic acid cyclopentane-1,3(5)- lactone (Vlll) in 5 ml. of ethanol is added 0.13 g. of sodium boron hydride and the mixture is stirred for 20 minutes under ice cooling. After completion of the reaction, 5% aqueous acetic acid is added to the reaction mixture to decompose the excess sodium boron hydride. A saturated aqueous sodium chloride solution is added to the reaction mixture and the mixture is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off to give 0.66 g. of the desired product as oil.

lR. (liquid film) cm: 1740, 1050 1l-hydroxy-2-[3-(Z-tetrahydropyranyl)-oxy-trans-1- octenyl]-3-acetic acid cyclopentane- 1 ,3(8)-lactone (X).

To a solution of 0.14 g. of 1-hydroxy-2-(3- hydroxytrans-1-octenyl)-3-acetic acid cyclopentanel,3(8)-lactone (1X) in 3 m1. of benzene is added 1 ml. of dihydropyran under ice cooling. To the mixture is added under ice cooling a solution prepared by dissolving 5 mg. of p-toluenesulfonic acid in 2 ml. of benzene under heating.

After completion of the addition, the temperature of the reaction mixture is slowly elevated to room temperature with stirring. After completion of the reaction, the solvent is distilled off to give oily residues. The residues obtained are subjected to column chromatography using 5 g. of aluminum (Grade 11, a product of Woelm Co.) and eluted with some amount of hexane 40% solution of benzene in hexane and next successively with 50-70% solution of benzene in hexane. The eluates with the latter solvent are collected and the solvent is distilled off to give 0.16 g. of the desired product .as oil.

LR. (liquid film) v cm: 1745,1015 N.M.R. comm; ppm 4.63-4.35 (2l-l,multiplet,

Mass spectrum M 336 (C H O 7. 2-{ 2B-[ 3-( Z-tetrahydropyranyl )oxy-transl octenyl 3a-hydroxycyclopentl a-yl }-ethanal (ll) equilibrium mixture with l-hydroxy-2-[ 3-( 2-tetrahydropyranyl )oxyl transoctenyl] -3-acetaldehydecyclopent-l ,3( 8 )-lactol (XI In 10 ml. of toluene is dissolved 502 mg. of lhydroxy-2-[3-(2-tetrahydropyranyl)oxy-trans-1- octenyl] 3-acetic acid cyclopentane-l ,3 8)-lactone (X) and to the solution is added a solution of 0.85 g. of diisobutylaluminum hydride in 61.5 g. of toluene at 60C.--70C. in an argon atmosphere followed by stirring for 2 hours. After completion of the reaction, a saturated aqueous sodium sulfate is added to the reaction mixture and the mixture is extracted with ethyl acetate.

The solvent is distilled off to give 543 mg. of the desired product as oil.

LR. (liquid film) v cm: 3420, 2750, 1725, 1015,

970 Mass spectrum M 338 (C l-l O '8. 2-[ 2B-( 3-hydroxyl trans-octenyl)3a-hydroxycyclopentl a-yl Iethanol (ll) In 50 ml. of a mixture of water, acetic acid and tetrahydrofuran (35:30:35) is dissolved 413 mg. of 2-{2B- [3-( Z-tetrahydropyranyl )oxy-transl -octenyl 3 ahydroxycyclopent-la-yl ethanal and the solution is stirred at 40-50C. for 4 hours.

After completion of the reaction, the solvent is distilled off under reduced pressure. Oily residues obtained are subjected to column chromatography using 4 g. of silica gel and eluted successively with benzene and 13% solution of ether in benzene, respectively. The eluates with the latter solvent are collected and the solvent is distilled off to give 120 mg. of the desired product as oil.

LR. (liquid film) v cm' 3450, 1720, 970

Mass spectrum M": 254 (C d-1 The following examples are presented to further illustrate the present invention.

EXAMPLE 1 15Tetrahydropyranyloxyprosta-S (cis) l3( trans)-dienoic acid In4.5 ml. of dimethyl sulfoxide is dissolved 4.05 g. of S-triphenylphosphonio pentanoic acid bromonium salt. To the solution is added 8.3 ml. of a solution which is prepared by adding 0.96 g. of sodium hydride (50% content) to ml. of dimethyl sulfoxide and stirring the mixture at 70C. for 2 hours. The mixture is stirred at room temperature for minutes and added to 2 ml.

of dimethyl sulfoxide solution containing 320 mg. of 2-[2B( 3-tetrahydropyranyloxy- 1 -(trans)-octenyl) cyclopent-la-yl]ethanal. The solution is stirred at room temperature for 30 hours. After completion of the reaction, the reaction mixture is poured into ice water. The mixture is adjusted to pH3 by addition of oxalic acid and extracted with ethyl acetate 4 times. The extract is'dried over anhydrous sodium sulfate and the solvent is distilled off to give 290 mg. of an oil. The oil is chromatographed on 5 g. of silica gel and eluted successively with benzene for a while and next benzene containing 2l0% ether.

The eluates with the latter solvent are collected and the solvent is distilled off to give 140 mg. of the pure desired product as oil.

N.M.R. (CDCl )8: ppm

8.2 (1H, broad, singlet, COO li) 5.5 (4H, broad, H

5 o THP and COOH H E m EXAMPLE 2 l5-Hydroxyprosta-5 (cis), l3 (trans)-dienoic acid In 3 ml. of dimethyl sulfoxide is dissolved 0.34 g. of sodium hydride (50% content) and the solution is stirred at C for 1.5 hours.

To the solution is added 450 mg. of 5- triphenylphosphonio pentanoic acid bromonium salt. To the solution thus obtained is added 93 mg. of 2-[2B- (3-hydroxy-l(trans)-octenyl) cyclopent-la-yl] ethanal in 1 ml of dimethyl sulfoxide. The solution is stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture is poured into ice water. The mixture is adjusted to pH3 by addition of oxalic acid and extracted with ether 3 times. The extract is dried over anhydrous sodium sulfate and the solvent is distilled off to give 230 mg. of an oil. The oil is chromatographed on 3 g. of silica gel and eluted successively with benzene for a while and next with benzene solution containing 1-5% ether.

The eluates with the latter solvent are collected and the solvent is distilled off to give 62 mg. of the pure desired product as oil.

l.R. (liquid film )vmax"" 3300-3400, 1710, 970

6.6 (2H, singlet, COOH, Ol-l) 5.4 (4H, broad, M

11oz, 15-lDihydroxyprosta-5 (cis), 13 (trans)-dienoic acid in ml. of dimethyl sulfoxide is dissolved 261 mg. of 2-[2,B-( 3-hydroxy- 1 (trans )-octenyl )-3ozhydroxycyclopent-loz-yl]ethanal [equilibrium mixture with 1-hydroxy-2-[ 3-hydroxy- 1 (trans )-octenyl) -3- acetaldehyde-cyclopent-l .3(5)-lactol]. To the solution is added 1.78 g. of sodium S-triphenylphosphonio pentanoate in 12 ml. of dimethyl sulfoxide (0.37 mole concentration dimethyl sulfoxide solution of sodium 5- triphenylphosphonio pentanoate). The mixture is stirred at room temperature for 3 hours. After completion of the reaction, an 5% aqueous acetic acid solution is added to the reaction mixture. The mixture is extracted with ether. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off. The residue is chromatographed on 3 g. of silica gel and eluted successively with benzene fora while and next benzene solution containing 1-20% ether.

The eluates with the latter solvent are collected and the solvent is distilled off to give 40 mg. of the desired product as oil.

l.R. (liquid film)vmax" 3360, 3020, 1710, 970 NMJR. ('CDCL'QTI ppm 9.12 (3H, triplet, C ll;i

6.00 (2H, broad,

Mass spectrum 1V1": 338.47(C l-1 O EXAMPLE 4 1 la-hydroxy--(Z-tetrahydropyranyl)oxyprosta- 5(cis), 13(trans)-dienoic acid in 8 ml. of dimethyl sulfoxide is dissolved 500 mg. of 2-{2B-[3-(Z-tetrahydropyranyl)oxy-1(trans)-octenyl]- 3ot-hydroxycyclopent-la-yl}ethanal (equilibrium mixture with 1-hydroxy-2-[3-(2-tetrahydropyranyl)oxy- 1(trans)octenyl]-3-acetaldehydecyclopent-1,3(5)- lactol).

To the solution is added 2.96 g. of sodium 5- triphenylphosphonio pentanoate in ml. of dimethyl sulfoxide (0.37 mole concentration dimethyl sulfoxide solution of sodium 5-triphosphonio pentanoate). The mixture is stirred at room temperature for 3 hours. After completion of the reaction, an 5% aqueous acetic acid solution is added to the reaction mixture. The mixture is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off. The residue is chromatographed on 1 g. of silica gel and eluted successively with benzene solution containing 20% ethanol and next with benzene solution containing -30% ether. The eluates with the latter solvent are collected and the solvent is distilled off to give 790 mg. of the desired product as oil.

l.R. (liquid film)1 max 3400, 1710, 1015 NMR. cbclm; ppm

4.7 4.4 (41-1, multiplet c=c u u /I H W MN and c=c l" tits Mass spectrum M 422 (C H O RlEhlERENTlAL EXAMPLE 1 Hydrolysis of l5-tetrahydropyranyloxyprosta-5(cis),

- 13(trans)-dienoic acid in a mixture of 2 ml. of acetic acid and 1 ml. of water is dissolved 91 mg. of 15-tetrahydropyranyloxyprosta- 5(cis), l3(trans)-dienoic acid and the solution is stirred at 30C for 3 hours. After completion of the reaction, the solvent is distilled off from the reaction mixture under reduced pressure to give 78 mg. of oil. The oil is chromatographed on 2g. of silica gel and eluted successively with benzene for a while and next benzene solution containing 2-20% ether. The eluates with the latter solvent are collected and the solvent is distilled off to give 69 mg'. of 15-hydroxyprosta-5(cis), 13(trans)- dienoic acid as oil. The infrared absorption spectrum,

2. Hydrolysis of 2-[ 2B-(3-tetrahydropyranyloxy-trans-1- octenyl)cyclopent 1 a-yl1ethanal ln a mixture of 1 ml. of tetrahydrofuran, 8 ml. of acetic acid and 1 ml. of water is dissolved 230 mg. of 2-[2B-(3-tetrahydropyranyloxy-trans-1- octenyl)cyclopent-10z-yl]ethanal and the solution is stirred at room temperature for 4 hours. After comple tion of the reaction, the solvent is distilled off from the reaction mixture under reduced pressure to give 240 mg. ofoil. The oil is chromatographed on 1.2 g. of silica gel and eluted successively with benzene for a while and next benzene solution containing l5% ether. The eluates with the latter solvent are collected and the solvent is distilled off to give 160 mg. of 2-[2B-(3- hydroxy-trans-l-octenyl) cyclopent lot-ynethanal as oil.

LR. (liquid film)vmax" 3450, 2700, 1740, 970

NlVLR. (CD096: ppm

9.21 (11H, broad singlet, C ll l O) 5.1 5.3 (2H, multiplet, H

3. Hydrolysis of 1 loz-hydroxy-15-(2-tetrahydropyranyl)oxyprosta- 5(cis), 13(trans)-dienoic acid In 30 ml. of a mixture of water, acetic acid, tetrahydrofuran (35:30:35) is dissolved 549 mg. of 1101- hydroxy-l S-(Z-tetrahydropyranyl) oxyprosta-S (cis), l3(trans)-dienoic acid and the solution is stirred at 40-50c for 3 hours. After completion of the reaction, the solvent is distilled off. The oily residue is chromatographed on 5 g. of silica gel and eluted successively with benzene for a while and next with benzene solution containing 120% ether. The eluates with the latter solvent are collected and the solvent is distilled off to give mg. of the desired product as oil. The infra- 15 red absorption spectrum, nuclear magnetic resonance spectrum and mass spectrum of the product thus ob tained are the same as those of the product obtained in Example 3.

4. Preparation of potassium l5-hydroxyprosta-5(cis), 13(trans)-dienoate In ml. of methanol is dissolved 305 mg. of l5-hydroxyprosta-5(cis), l3(trans)-dienoic acid and to the solution is added 75 mg. of potassium carbonate in 5 ml. of water. The mixture is stirred at room temperature for 3 hours. After completion of the reaction, the solvent is distilled off under reduced pressure to give 310 mg. of the desired product as oil.

LR. (liquid film)vmax"" 3350, 1570, 1400, 980

5. Preparation of potassium 110:, l 5-dihydroxyprosta-5(cis), 1 3(trans)-dienoate In 10 m]. of methanol is dissolved 350 mg. of lla, l5-dihydroxyprosta-5(cis), l3(trans)-dienoic acid and to the solution is added 78mg. of potassium carbonate in 5 ml. of water. The mixture is stirred at room temperature for 3 hours. After completion of the reaction, the solvent is distilled off under reduced pressure to give 360 mg. ofv the desired product as oil.

LR. (liquid film)vmax 3400, 1570, 1400, 980

What is claimed is:

l. A l 1,1 S-dihydroxyprosta-S(cis),l 3(trans)-dienoic acid having the formula lS-dihydroxyprosta-S(cis), l3(trans)-dienoate.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT N0. 3,894,009 Page 1 of 2 DATED July 8, 1975 |NV.ENTOR(5) KIYOSHI SAKAI et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

First page, second Column, line 9: replace "protaglandin" with prostaglandin Column 1, line 61: after "calcium", replace the comma r") with a semicolon Columns 5-6, Compounds (IX) and (X) at "R-CH-X" the bond to "OH" (in Comp. IX) and to "O-THP" (in Comp. X) should be a wavy line g Column 6, Compound (X): insert a single bond between "0" and "THP".

Column 7, Compound (II) (second occurrence) should be Columns 7-8, Compounds (XI) (II) and (II) at I'R-CH--X" (XI) and "X-CH-R" (II and II' the bond to "O-THP" (XI and II) and ".OH" (11' should be a wavy line i UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,894,009 Page 2 of 2 DATED July 8, 1975 lN\/ ENTOR(S) KIYOSHI SAKAI et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Columns 7-8, Compounds (XI) (II) and (II) insert a single bond between "0" and "THP" and between "X" II CH" II R" Column 9, line 40: replace "acidpyridine" with acid pyridine Column 12', lines 20-25, in the Compound: insert a single bond between "0" and "THP".

Column 12, line 57: at "COOH" and "OH", the "H" should be underscored with a wavy line Signed and Scaled this Twenty-fourth D a) of October 1978 [SEAL] Arrest:

RUTH C. MASON DONALD W. BANNER Amsn'ng Qfficer Commissioner of Patents and T rademarke 

1. A 11,15-DIHYDROXYPROSTA-5(CIS),13(TRANS)-DIENIC ACID HAVING THE FORMULA
 2. A compound of claim 1 comprising 1115-dihydroxyprosta-5(cis), 13(trAns)-dienoic acid.
 3. A compound of claim 1 comprising 11 Alpha -hydroxy-15-(2-tetrahydropyranyl)oxyprosta-5(cis), 13(trans)-dienoic acid.
 4. A compound of claim 1 comprising potassium 11 Alpha , 15-dihydroxyprosta-5(cis), 13(trans)-dienoate. 